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US5354758A - Benzomorphans useful as NMDA receptor antagonists - Google Patents

Benzomorphans useful as NMDA receptor antagonists Download PDF

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US5354758A
US5354758A US07/991,365 US99136592A US5354758A US 5354758 A US5354758 A US 5354758A US 99136592 A US99136592 A US 99136592A US 5354758 A US5354758 A US 5354758A
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hcl
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pharmaceutically acceptable
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John A. Lawson
Itsuo Uchida
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Japan Tobacco Inc
SRI International Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • C07D221/26—Benzomorphans

Definitions

  • the invention concerns a series of benzomorphan derivatives useful in the treatment of cerebrovascular disorders.
  • NMDA N-methyl-D-aspartate
  • This excitotoxic action is responsible for neuronal loss in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery and cerebral trauma.
  • the compounds of the invention which are active as competitive antagonists of NMDA receptor-mediated ion-channel activation, are thus useful in the treatment of the above disorders.
  • the compounds of the invention are also useful for treating neurodegenerative disorders, spinal cord injury, and poisoning by exogenous NMDA poisons (for example, some forms of lathyrism).
  • NMDA poisons for example, some forms of lathyrism.
  • the present compounds have benzomorphan structures. ##STR2##
  • R is a member selected from the group consisting of --CR 1 R 2 R 3 , hydroxy, an alkoxy group having from 1 to 4 carbon atoms and --NR 4 R 5 , in which
  • R 1 , R 2 and R 3 are hydrogen and the remainder are each independently selected from the group consisting of an alkyl group having from 1 to 4 carbon atoms, an alkenyl group having from 2 to 4 carbon atoms, an alkynyl group having from 2 to 4 carbon atoms, a cycloalkyl group having from 3 to 7 carbon atoms, a cycloalkylalkyl group having from 4 to 9 carbon atoms and a 3 to 6 membered cyclic ether;
  • R 4 and R 5 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms
  • R 6 and R 7 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms.
  • R 8 is hydrogen, an alkyl group having 1 to 4 carbon atoms, hydroxy, an alkoxy group having 1 to 4 carbon atoms or halogen;
  • this invention provides pharmaceutical compositions made up of one or more of these compounds with pharmaceutically acceptable carriers. These compositions are useful as N-methyl-D-aspartate receptor antagonists. In other aspects, this invention provides processes for preparing these compounds, and methods to treat cerebral diseases by administering to a patient an effective amount of these pharmaceutical compositions.
  • FIG. 1 is a general depiction of an overall scheme of chemical reactions which can be used to prepare compounds of the invention with --CR 1 R 2 R 3 as N-substituent.
  • FIG. 2 is a depiction of the chemical reactions employed in Example 1.
  • FIG. 3 is a depiction of the chemical reactions employed in Examples 2 and 3.
  • FIG. 4 is a depiction of the chemical reactions employed in Example 4.
  • FIG. 5 is a depiction of the chemical reactions employed in Example 5.
  • FIG. 6 is a depiction of the chemical reactions employed in Example 6.
  • FIG. 7 is a depiction of the chemical reactions employed in Example 7.
  • FIG. 8 is a depiction of the chemical reactions employed in Example 8.
  • FIG. 9 is a depiction of the chemical reactions employed in Example 9.
  • FIG. 10 is a depiction of the chemical reactions employed in Example 10.
  • FIG. 11 is a depiction of the chemical reactions employed in Example 11.
  • FIG. 12 is a depiction of the chemical reactions employed in Example 12.
  • FIG. 13 is a depiction of the chemical reactions employed in Example 13.
  • FIG. 14 is a depiction of the chemical reactions employed in Example 14.
  • FIG. 15 is a depiction of the chemical reactions employed in Example 15.
  • FIG. 16 is a depiction of the chemical reactions employed in Example 16.
  • FIG. 17 is a depiction of the chemical reactions employed in Example 17.
  • the present invention provides compounds and pharmaceutical compositions based on them which are useful as N-methyl-D-aspartate receptor antagonists and in the treatment of cerebral diseases such as cerebral ischemia, cerebral hypoglycemia, epilepsy, anxiety and convulsion.
  • R is a member selected from the group consisting of --CR 1 R 2 R 3 , hydroxy, an alkoxy group having from 1 to 4 carbon atoms and --NR 4 R 5 , in which
  • R 1 , R 2 and R 3 are hydrogen and the remainder are each independently selected from the group consisting of an alkyl group having from 1 to 4 carbon atoms, an alkenyl group having from 2 to 4 carbon atoms, an alkynyl group having from 2 to 4 carbon atoms, a cycloalkyl group having from 3 to 7 carbon atoms, a cycloalkylalkyl group having from 4 to 9 carbon atoms and a 3 to 6 membered cyclic ether;
  • R 4 and R 5 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms
  • R 6 and R 7 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms.
  • R 8 is hydrogen, an alkyl group having 1 to 4 carbon atoms, hydroxy, an alkoxy group having 1 to 4 carbon atoms or halogen;
  • an alkyl group having 1 to 4 carbon atoms is defined to include straight or branched chain alkyl groups having from 1 to 4 carbon atoms. These include --CH 3 , --CH 2 CH 3 , --(CH 2 ) 2 CH 3 , --CH(CH 3 ) 2 , --(CH 2 ) 3 CH 3 , --CH 2 CH(CH 3 ) 2 , --CH(CH 3 )CH 2 CH 3 , and --C(CH 3 ) 3 .
  • an alkenyl group having 2 to 4 carbon atoms is defined to include straight or branched chain alkenyl groups having from 2 to 4 carbon atoms with 1 or 2 olefin unsaturations.
  • an alkynyl group having 2 to 4 carbon atoms is defined to include straight or branched chain alkynyl groups having from 2 to 4 carbon atoms with 1 or 2 acetylenic unsaturations and up to 1 olefinic unsaturation.
  • a cycloalkyl group having 3 to 7 carbon atoms includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • a cycloalkylalkyl group having 4 to 9 carbon atoms includes groups such as, for example, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclopropylpentyl, cyclopropylhexyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclobutylbutyl, cyclobutylpentyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclopentylbutyl, cyclohexylmethyl, cyclohexylethyl
  • a 3- to 6-membered cyclic ether includes groups having 2 to 5 cyclic carbons and a cyclic ether oxygen. Such groups include, for example, ##STR7##
  • an alkoxy group having 1 to 4 carbon atoms is defined to include groups such as methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, sec-butoxy, tert-butoxy.
  • halogen is defined to include the fluorine, chlorine, bromine and iodine organic substituent groups.
  • R is --CR 1 R 2 R 3 , an alkoxy group having 1 to 4 carbon atoms or --NR 4 R 5 in which at most one of R 1 , R 2 and R 3 is hydrogen and the remainder of R 1 , R 2 and R 3 are each independently an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a cycloalkylalkyl having 4 to 9 carbon atoms or a 3 to 6 membered cyclic ether; R 4 and R 5 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms; R 6 and R 7 are each independently an alkyl group having 1 to 4 carbon atoms, and R 8 is hydrogen, hydroxy, an alkoxy group having 1 to 4 carbon atoms or halogen.
  • R is --CR 1 R 2 R 3 , methoxy, ethoxy, propoxy, or --NR 4 R 5 in which at most one of R 1 , R 2 and R 3 is hydrogen, and the remainder of R 1 , R 2 and R 3 are each independently methyl, ethyl, propyl, ethenyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, ##STR8##
  • R 4 and R 5 are each independently hydrogen, methyl, ethyl, propyl;
  • R 6 and R 7 are each independently methyl, or ethyl and R 8 is hydrogen, methyl, hydroxy, methoxy, chlorine or fluorine.
  • the tertiary amine group present in the compounds of the invention can form acid-addition salts of pharmaceutically acceptable inorganic or organic acids, such as of strong mineral acids, for example, hydrohalic, hydrochloric or hydrobromic acid; sulfuric, phosphoric or nitric acid; aliphatic or aromatic carboxylic or sulfonic acids, for example, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, gluconic, citric, ascorbic, maleic, fumaric, pyruvic, palmoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic or naphthalenesulfonic acid.
  • pharmaceutically acceptable inorganic or organic acids such as of strong mineral acids, for example, hydrohalic, hydrochloric or hydrobromic acid; sulfuric, phospho
  • the compounds of the invention contain at least two asymmetric carbon atoms.
  • the invention includes individual enantiomers, diastereomers, or mixtures thereof, which may be prepared or isolated by methods known in the art.
  • the invention includes individual (+)-and (-)- optical isomers derived from the benzomorphan skeleton and mixtures thereof, which may be prepared or isolated by the methods known in the art. Usually the (+)-isomers are more active with less side effects. For this reason they are preferred.
  • a material is considered to be "substantially isomerically pure" (such as optically and geometrically pure) when it contains at least about 75% and preferably 85% or especially at least about 90% isomerical purity.
  • the compounds of the invention have pharmacological advantages which render them useful for treating cerebrovascular diseases.
  • one or a mixture of two or more of these compounds may be administered according to any convenient or effective methods for introducing foreign substances into the blood stream of mammals, such as by oral, rectal, nasal, buccal, vaginal, or parenteral routes.
  • the effective dosage level is, for example, 0.01 to 100 mg/kg, preferably about 0.05 to 50 mg/kg. Doses of this size may be administered on a regimen of 1 to 4 times per day.
  • the pharmaceutical formulations comprising the compounds of the invention may be in dosage forms such as tablets, pills, capsules, powders, or granules for oral administration.
  • compositions can be formulated into pharmaceutical compositions by admixture with pharmaceutically acceptable nontoxic carriers.
  • such compositions may be prepared for use for parenteral (subcutaneous, intramuscular or intravenous) administration particularly in the form of liquid solutions or suspensions; for use in vaginal or rectal administration particularly in semisolid forms such as creams and suppositories; for oral or buccal administration particularly in the form of tablets or capsules; or intranasally particularly in the form of powders, nasal drops or aerosols.
  • compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. 1975, incorporated by reference.
  • Formulations for parenteral administration may contain as common excipients, sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
  • Formulations for vaginal or rectal administration, e.g., suppositories may contain as excipients, for example, polyalkylene glycols, petroleum jelly, cocoa butter, and the like.
  • Formulations for inhalation administration may be solid and contain as excipients, for example, lactose, or may be aqueous or oily solutions for administration in the form of nasal drops.
  • excipients include sugars, calcium stearate, magnesium stearate, pregelatinated starch, and the like.
  • a pharmaceutically acceptable nontoxic composition can be formed by the incorporation of any of the normally employed excipients, oral dose extenders or carriers such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the like.
  • Such compositions can take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained-release formulations, and the like.
  • Such compositions may contain 0.1-95% active ingredient, preferably 1-70%, with the remainder being carrier.
  • the materials of this invention can be employed as the sole active agent in a pharmaceutical composition or can be used in combination with other active ingredients.
  • the effects of the compounds of the invention can be evaluated in in vitro tests or in vivo animal tests using mammals such as mice, rats, rabbits, dogs and monkeys, or tissues or enzyme preparations thereof.
  • NMDA receptor Competition binding for NMDA receptor with radio-labeled known NMDA antagonist is one convenient way to ascertain the ability of the compounds of the invention to bind to target cerebral cells. This evaluation can be made according to the method of J. Lehman et al., 1988. In addition, the ability to antagonize NMDA receptors can be evaluated according to the method of Ferkany et al., 1988.
  • the compounds of this invention are new materials. As such they can not be purchased and must be prepared.
  • Intermediate 2 can be converted directly to the desired product 4 by adding an R 1 R 2 C ⁇ O (ketone) in the presence of a sodium cyanoborohydride (NaCNBH 3 ), and the like at 50° to 100° C.
  • R 1 R 2 C ⁇ O ketone
  • NaCNBH 3 sodium cyanoborohydride
  • intermediate 2 is reacted with a cyanohydrin, R 1 --CH(OH)CN or R 1 R 2 --C(OH)CN to afford product 3 or 3' respectively. Thereafter, the intermediate 3 or 3' can be converted to the desired product 4 or 4' respectively via Grignard reaction by adding R 2 --MgBr or R 3 13 MgBr in tetrahydrofuran (THF).
  • THF tetrahydrofuran
  • the above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures, and under atmospheric or super-atmospheric pressure.
  • diluents preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures, and under atmospheric or super-atmospheric pressure.
  • the invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure antipodes.
  • Reaction Scheme 3 (FIG. 3) corresponds to Examples 2 and 3, and
  • Reaction Schemes 4-17 correspond to Examples 4-17 respectively.
  • the Grignard diene intermediate was then efficiently reduced to the corresponding 2-benzyl-1,3,4-trimethyl-1,2,5,6-tetrahydropyridine analog.
  • the reaction mixture was refluxed for 2 hrs and then cooled to room temperature.
  • the reaction mixture was quenched by the slow addition of concentrated HCl until a pH of 2 was maintained.
  • the ethanol was evaporated at reduced pressure, the resultant residue was dissolved in ether and water.
  • the aqueous phase was separated and brought to pH 11 by the portionwise addition of solid NaOH pellets.
  • the aqueous phase was extracted with ether.
  • the ether solution was dried over MgSO 4 and evaporated to dryness at reduced pressure to afford 200 g of crude 2-benzyl-1,3,4-trimethyl-1,2,5,6-tetrahydropyridine (59% yield).
  • (+)-IIId-7 and (+)-IIId-7.HCl can be prepared in the following two ways, Method A and Method B. Method B gives a higher yield.
  • (+)-IIId-4.HCl (0.53 g, 2.09 mmol, Example 2) in 40 mL methylcyclopropyl ketone at 93° C. under argon was added with stirring NaCNBH 3 (2.00 g, 31.7 mmol). Then glacial acetic acid was added dropwise until H 2 evolution ceased over an approximately 2 hr period. Following a routine workup, the crude product was purified by flash chromatography (silica gel/ethyl acetate). The isolated free base (+)-IIId-7 was dissolved in ether and precipitated as the HCl salt by addition of HCl/ether solution: (+)-IIId-7.HCl, wt. 0.32 g, 47% yield.
  • (+)-IIId-7 was recovered as a mixture of diastereomers, 1.40 g, 5.2 mmol, yield 83%.
  • the product (+)-IIId-7.HCl precipitated as a white powder from ether, 1.41 g, yield 77%.
  • (+)-BZ-1 1 H NMR: (CDCl 3 , 300 MHz) ⁇ 6.95-6.70 (m, 4H, aromatic), 3.40 (brs, 1H, C 1 --H), 1.08 (s, 3H, C 5 --CH 3 ), 0.52 (d, 3H, C 9 --CH 3 ), 0.30-0.00 (m, 10H, cyclopropyl). MS: m/z 295 (parent ion), 280 (M-CH 3 ), 254 (M-cyclopropyl).
  • MS: m/z 255 (parent ion), 240 (M-CH 3 ), 228 (M-vinyl).
  • (+)-BZ-4 1 H NMR (CDCl 3 , 300 MHz) ⁇ 7.25-7.00 (m, 4H, aromatic), 5.90-5.70 (m, 1H, vinyl), 5.10-4.88 (m, 2H, vinyl), 1.38 (s, 3H, C 5 --CH 3 ), 0.86, 0.81 (2d, 3H, C 9 --CH 3 (isomers)), 0.80-0.00 (m, 5H, cyclopropyl)
  • MS: m/z 281 (parent ion), 266 (M-CH 3 ), 254 (M-vinyl), 240 (M-cyclopropyl).
  • trans-2-buten-1-ol was stereoselectively epoxidized with t-butyl hydroperoxide in dichloromethane in the presence of catalytic L-(+)-diethyltartrate and titanium (IV) isopropoxide.
  • a second approach to the epoxyamine (+)BZ-5 involves reaction of 0.60 g (3.0 mmol) of (+)IIId-4 (Example 2) with 0.55 g (3.5 mmol) of the cyanohydrin, which was prepared by protection of glycerol as the acetonide (Org. Syn., Coll. vol. 2, p. 502), followed by Swern oxidation of the free alcohol and treatment of the aldehyde with acetone cyanohydrin and catalytic triethylamine.
  • (+)-BZ-10.HCl was prepared in the manner of the synthesis of (+)-IIId-4.HCl (FIG. 2 and 3) using p-fluorobenzylmagnesium bromide instead of benzylmagnesium chloride.
  • (+)IIId-4.HCl (Example 2) (0.521 g, 2.19 mmol) in CHCl 3 (40 mL) was treated with ethyl acrylate (0.438 g, 20 eq) and triethylamine (0.66 g, 3.0 eq) at reflux for 16 h. TLC then showed nearly complete conversion to a new, nonpolar product. After filtration through a silica pad and spin evaporation, the adduct 11 was recovered as a colorless oil (0.49 g, 74%).
  • (+)BZ-17A 0.296 g, 89%).
  • (+)BZ-17A (0.20 g, 1.36 mmol) in ether with HCl/ether produced (+)BZ-17A.HCl as a white powder (0.274 g, 79%).
  • (+)IIId-4.HCl (Example 2) (0.60 g, 2.52 mmol) was dissolved in 70 m/L of methanol and treated with a solution of K 2 CO 3 (2.1 g, 15.2 mmol) in 20 mL of H 2 O and heated to reflux. Then hydroxylamine-O-sulfonic acid (H 3 N + -OSO 3 - , 0.42 g, 3.07 mmol, 1.5 eq) was added in 3 equal portions (0.14 g) over 20 min.
  • reaction mixture was filtered to remove insoluble inorganic salts (K 2 SO 4 ), the filtrate was spin-evaporated to remove methanol, and the aqueous residue was partitioned in CH 2 Cl 2 /H 2 O.
  • the organic layer containing 12, unreacted (+)IIId-4, and other by-products was spin-evaporated to give a yellow oily residue (0.48 g).
  • This material was immediately dissolved in 10 mL of H 2 O, acidified to pH 3, and treated with 1.0 mL of 37% aqueous formalin, followed by NaCNBH 3 (0.49 g, 7.6 mmol). TLC after 5 min showed that no 12 or (+)IIId-4 remained.
  • (+)BZ-18 was isolated along with (+)IIId-5 (Example 1) (resulting from N-methylation of IIId-4). Filtration through silica readily separated the less polar (+)BZ-18 from (+)IIId-5 (eluting with CH 2 Cl 2 , then ether) to afford pure (+)BZ-18 (0.28 g, 1.14 mmol, 45% from (+)IIId-4.HCl).
  • (+)-BZ-23.HCl was prepared in the manner of the synthesis of (+)-IIId-4.HCl (FIG. 2 and 3) using p-chlorobenzylmagnesium bromide instead of benzylmagnesium chloride.
  • (+)-BZ-22.HCl was prepared in the manner of the synthesis of (+)-IIId-4.HCl (FIG. 2 and 3) using p-methylbenzylmagnesium bromide instead of benzylmagnesium chloride.
  • glycine final concentration 50 ⁇ M
  • glutamate 50 ⁇ M
  • Varying concentrations of the test compounds 100 ⁇ L
  • [ 3 H]MK-801 100 ⁇ L, final concentration 3 nM
  • the incubation was terminated by rapid filtration (Brandel Cell Harvester) over Whatman GF/B filters, which were then washed twice with 5 mL of 5 mM Tris-HCl. Radioactivity trapped on the filters was counted in 5 mL Scintiverse II at 50% efficiency in 7 mL minivials after standing at room temperature overnight. Unlabeled MK-801 (100 ⁇ M) was used to estimate nonspecific binding.
  • test compounds 200 ⁇ L
  • [ 3 H]DAGO 100 ⁇ L, final concentration 2 nM
  • Unlabeled DAGO final concentration 10 ⁇ M
  • the reaction was stopped by filtration through GF/B filters using a Brandel Cell Harvester. After washing twice with 5 mL of ice cold buffer, the filters were suspended in 5 mL scintillation fluid, and the radioactivity was counted after standing at room temperature overnight.
  • Hartley guinea pigs were decapitated, and the brains were removed and homogenized in 20 volumes of 50 mM Tris-HCl using a Polytron homogenizer. The homogenate was centrifuged at 27,000 ⁇ G for 15 minutes, and the pellet was resuspended in 50 mM Tris-HCl. The centrifugation procedure was repeated twice. The pellet was diluted to approximately 8 mg wet tissue/assay. Various concentrations of the test compounds (100 ⁇ L) and [ 3 H]PPP (100 ⁇ L, final concentration 0.6 nM) were incubated with 1.8 mL of the tissue homogenate at 25° C. for 1 hour.
  • Unlabeled PPP (final concentration 10 ⁇ M) was added to some tubes to determine nonspecific binding. The reaction was stopped by filtration through GF/B filters using a Brandel Cell Harvester. After washing twice with 50 mM of ice cold Tris-HCl, the filters were suspended in 5 mL of scintillation fluid, and the radioactivity was counted after standing at room temperature overnight.
  • Table 1 summarizes the results of the in vitro binding studies using these three radioligands at the NMDA receptor site, ⁇ -site and ⁇ -site of opioid receptor, respectively.
  • K i values were calculated from the following equation: ##EQU1## where K d values for [ 3 H]MK-801, [ 3 H]DAGO and [ 3 H]PPP are 5.6 nM, 2.0 nM and 20 nM, respectively.
  • the test compounds were administered ip to four male Swiss-Webster mice (26-34 g) each, following 30 minutes later, 200 mg/kg of NMDA was administered to the mice each.
  • the LD 50 of NMDA was found to be 164 mg/kg, and approximately 90% of the mice died at 200 mg/kg.
  • Those compounds that protected three or more of the mice at any of the doses were evaluated further by determining the ED 50 values using three or more doses with the eight mice per dose.
  • the ED 50 was estimated by the method of Litchfield and Wilcoxin (1949). Water-soluble compounds were dissolved in distilled water and administered in a volume of 10 ml/kg. Water-insoluble compounds were suspended in an aqueous solution of 0.5% methyl cellulose and administered in a volume of 20 ml/kg.
  • compositions can be formed as follows:

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US20050113361A1 (en) * 2000-10-24 2005-05-26 Csilla Horvath Amide derivatives as NMDA receptor antagonists
US20050261329A1 (en) * 2002-05-17 2005-11-24 Jenken Biosciences, Inc. Opioid and opioid-like compounds and uses thereof
US20060142186A1 (en) * 2004-12-23 2006-06-29 Voyager Pharmaceutical Corporation Leuprolide acetate and acetylcholinesterase inhibitors or NMDA receptor antagonists for the treatment of alzheimer's disease
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